[Retracted] Protein Arginine Methyltransferase 5 Promotes the Migration of AML Cells by Regulating the Expression of Leukocyte Immunoglobulin‐Like Receptor B4

Abstract

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults with poor prognosis. Especially for AML-M5 type, due to the strong cell migration ability, the possibility of extramedullary invasion is large and widespread, which leads to poor therapeutic effect. Previous studies have found that protein arginine methyltransferase 5 (PRMT5) could promote the proliferation and differentiation of leukemic cells in AML, but its regulation on the invasive ability of AML cells remains unclear. This study was designed to explore the role of PRMT5 in regulating the invasion of AML cells and to investigate the mechanisms. Patient samples were collected for detection of PRMT5 expression level. AML cells were used for exploring the function of PRMT5. The results of clinical samples showed that the expression of PRMT5 was significantly increased in newly diagnosed and recurrent AML patients, and the expression of leukocyte immunoglobulin-like receptor B4 (LILRB4) was positively correlated with the level of PRMT5. In the cell experiment in vitro, we found that when PRMT5 was knocked down, the invasion, migration, and adhesion capacities of MV-4-11 cells and THP-1 cells were decreased, and the mRNA and protein levels of LILRB4 were also decreased. Moreover, we screened related signaling pathways and found that PRMT5 affected the expression of downstream LILRB4 by activating mTOR pathway, which in turn enhanced the invasive ability of AML cells. Taken together, PRMT5 plays an important role in the invasion of AML, which acts via regulating the expression of LILRB4. PRMT5 could act as a potential therapeutic candidate for AML.

PRMT5 regulates ATF4 transcript splicing and oxidative stress response

“…PRMT5 function is essential for normal hematopoiesis [ 17 , 53 ], maintenance of chronic myelogenous leukemia stem cells [ 54 ], differentiation regulation in acute lymphocytic leukemia [ 55 ], leukemia cell migration [ 56 ], and survival of leukemia with MLL rearrangements and splicing factor mutations [ 8 , 10 , 21 ]. Our findings on PRMT5 inhibition leading to cell cycle arrest and senescence are consistent with previous reports in glioblastoma, AML, and other cancers [ 8 , 32 , [57] , [58] , [59] ].…”

Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies

“…Patients with newly diagnosed or recurrent AML display an increased expression of PRMT5 , and a positive correlation is found with the expression of the leukocyte immunoglobulin-like receptor B4 ( LILRB4 ). LILRB4 expression is triggered by the activation of the mTOR pathway by PRMT5, enhancing the invasion of AML cells [ 84 ].…”

LILRB4, an immune checkpoint on myeloid cells

“…Furthermore, FTO-specific inhibitors reduce the expression of LILRB4 and PD-L1/2 on AML cells, substantially increasing the sensitivity of AML cells to be killed by activated T cells 107 . In addition, protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes symmetric demethylation of protein arginine residues, regulates epigenetic activity by targeting histone proteins 108,109 . LILRB4 expression is upregulated by PRMT5 in AML cells, which results in activation of the mTOR pathway to enhance the invasion ability of AML cells 109 .…”

“… 107 In addition, protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes symmetric demethylation of protein arginine residues, regulates epigenetic activity by targeting histone proteins. 108 , 109 LILRB4 expression is upregulated by PRMT5 in AML cells, which results in activation of the mTOR pathway to enhance the invasion ability of AML cells. 109 LILRB4 is specifically expressed on monocytic AML cells but not on normal hematopoietic progenitor cells and anti-tumor T cells, which makes LILRB4 a promising therapeutic target to overcome the disadvantages of previous AML antigens, such as CD123 and CD33, causing severe bone marrow toxicity.…”

“… 108 , 109 LILRB4 expression is upregulated by PRMT5 in AML cells, which results in activation of the mTOR pathway to enhance the invasion ability of AML cells. 109 LILRB4 is specifically expressed on monocytic AML cells but not on normal hematopoietic progenitor cells and anti-tumor T cells, which makes LILRB4 a promising therapeutic target to overcome the disadvantages of previous AML antigens, such as CD123 and CD33, causing severe bone marrow toxicity. 35 , 102 Therefore, several therapeutic strategies have been developed, including anti-LILRB4 humanized monoclonal antibodies, 105 anti-LILRB4 chimeric antigen receptor (CAR)-T cells 110 and anti-LILRB4 antibody-drug conjugates (ADCs), 111 and biomimetic inhibitors.…”